Copper-catalyzed 6-endo cyclization of N-propargylic β-enaminocarbonyls was developed for the synthesis of oxidation-labile 1,6-dihydropyridines. This synthetic method allows flexible and regio-defined assembly of various substituents at the N1, C2, C3, C4, and C6 positions of 1,6-dihydropyridines under mild conditions.

While metal-promoted activation of tertiary alkyl halides often causes elimination and hydrodehalogenation, we have developed a nickel-catalyzed reductive dimerization that allows the generation of a potently reactive tertiary radical equivalent to form a very congested C(sp3)–C(sp3) bond even below room temperature. The catalytic protocol is applicable to the dimerization of several pyrrolidinoindoline scaffolds through an appropriate choice of catalyst to accommodate different substrate reactivities with functional group compatibilities. The efficiency of the nickel-catalyzed protocol was successfully demonstrated through a systematic total synthesis of chimonanthines, folicanthines and (+)-WIN 64821.

Assembly of four components through sequential [6+2], [2+2], and [3+2] annulations on an azulenone manifold allows for five-step access to a natural product-inspired scaffold with exquisite control of the ten consecutive stereocenters. X-ray analysis was used to define the spatial arrangement of the three fragments and functional groups on this rigid scaffold.

We have developed a unique catalytic protocol for direct gem-vinylation of tryptamine derivatives employing Hg(OTf)2 as the optimum catalyst. The intermolecular vinylations with a series of aromatic acetylenes proceeded under ambient temperature at the C2 positions of indoles with high functional group tolerance. Based on the mechanistic insights, we further developed the tandem reactions successfully constructing a quaternary center.

To access high-quality small-molecule libraries to screen lead candidates for neglected diseases exemplified by human African trypanosomiasis, we sought to develop a synthetic process that would produce collections of cyclic scaffolds relevant to an assortment of natural products exhibiting desirable biological activities. By extracting the common structural features among several sesquiterpenes, including artemisinin, anthecularin, and transtaganolides, we designed six types of scaffolds with systematic structural variations consisting of three types of stereochemical relationships on the sp3 ring-junctions and two distinct arrays of tricyclic frameworks. A modular and stereodivergent assembly of dienynes exploiting a versatile manifold produced a series of cyclization precursors. Divergent cyclizations of the dienynes employing tandem ring-closing metathesis reactions overrode variant reactivities of the cyclization precursors, leading to the six canonical sets of the tricyclic scaffolds incorporating a diene group. Screenings of trypanosomal activities of the canonical sets, as well as regio- and stereoisomers of the tricyclic dienes, allowed generation of several anti-trypanosomal agents defining the three-dimensional shape of the pharmacophore. The candidate tricyclic dienes were selected by primary screenings and further subjected to installation of a peroxide bridge, which generated artemisinin analogues that exhibited potent in vitro anti-trypanosomal activities comparable or even superior to those of artemisinin and the approved drugs, suramin and eflornithine.

Dense and stereo-controlled integrations of C–N bonds on the azulenone scaffold are achieved by sequential (i) ene, (ii) [6+2]-cycloaddition, and (iii) hetero-conjugate addition reactions leading to a topologically complex bis-bridged skeleton.

We report the development of a divergent synthetic process entailing four-step access to the elaborate fused skeletons reminiscent of aspidophytines and transtaganolides. A variety of branched precursors were synthesized on the basis of Ugi condensations and installation of diazoimide and subjected to rhodium-catalyzed tandem reactions. Switching of cyclization modes was demonstrated by the choice of the amine building blocks installed at site C.

Excised thioesterase domains are versatile catalysts for macrocyclization. However, thioesterase-catalyzed cyclization is often precluded due to the occurrence of hydrolysis and product inhibition. To circumvent these obstacles, we devised an unprecedented strategy: coincubation with DNA to capture the cyclic products possessing DNA-binding properties. In experiments involving echinomycin thioesterase-catalyzed macrolactonization leading to the cyclic triostin A analog TANDEM, we found that the addition of DNA drastically improved the yield of TANDEM (19% → 67%), with a complete reversal of the cyclization:hydrolysis ratio (1:2 → 18:1). Furthermore, the applicability of this protocol was demonstrated for a variety of substrates. The results described herein provide insight into the mechanism of echinomycin thioesterase-catalyzed conversions and also pave the way for chemoenzymatic synthesis of the quinoxaline antibiotics and their analogs.

Dense and stereo-controlled integrations of C–N bonds on the azulenone scaffold are achieved by sequential (i) ene, (ii) [6+2]-cycloaddition, and (iii) hetero-conjugate addition reactions leading to a topologically complex bis-bridged skeleton.

While metal-promoted activation of tertiary alkyl halides often causes elimination and hydrodehalogenation, we have developed a nickel-catalyzed reductive dimerization that allows the generation of a potently reactive tertiary radical equivalent to form a very congested C(sp3)–C(sp3) bond even below room temperature. The catalytic protocol is applicable to the dimerization of several pyrrolidinoindoline scaffolds through an appropriate choice of catalyst to accommodate different substrate reactivities with functional group compatibilities. The efficiency of the nickel-catalyzed protocol was successfully demonstrated through a systematic total synthesis of chimonanthines, folicanthines and (+)-WIN 64821.

Copper-catalyzed 6-endo cyclization of N-propargylic β-enaminocarbonyls was developed for the synthesis of oxidation-labile 1,6-dihydropyridines. This synthetic method allows flexible and regio-defined assembly of various substituents at the N1, C2, C3, C4, and C6 positions of 1,6-dihydropyridines under mild conditions.

We have developed a unique catalytic protocol for direct gem-vinylation of tryptamine derivatives employing Hg(OTf)2 as the optimum catalyst. The intermolecular vinylations with a series of aromatic acetylenes proceeded under ambient temperature at the C2 positions of indoles with high functional group tolerance. Based on the mechanistic insights, we further developed the tandem reactions successfully constructing a quaternary center.

Assembly of four components through sequential [6+2], [2+2], and [3+2] annulations on an azulenone manifold allows for five-step access to a natural product-inspired scaffold with exquisite control of the ten consecutive stereocenters. X-ray analysis was used to define the spatial arrangement of the three fragments and functional groups on this rigid scaffold.